Method of fabricating an implantable medical device comprising a rapamycin derivative

ABSTRACT

This invention relates to an method of manufacture of an implantable medical device comprising an oxygen-sensitive rapamycin derivative that is protected by addition of an antioxidant during the manufacturing process where the amount of antioxidant added at the outset of the processing is such that when the device is fully fabricated, sterilized and packaged the amount of antioxidant has reduced to a minimal, preferably non-detect, amount.

FIELD

This invention relates to a method of fabricating an implantable medicaldevice that includes a drug reservoir layer comprising a rapamycinderivative drug wherein the steps in the process minimize exposure ofthe drug to harsh processing conditions, eliminate the need to isolatethe drug as a dry solid, and ameliorate deterioration of the drug causedby the general oxygen-sensitivity of this class of drugs due to thepresence of a conjugated triene in their macrocyclic ring structure.

BACKGROUND

Until the mid-1980s, the accepted treatment for coronaryatherosclerosis, i.e., narrowing of the coronary artery(ies) wascoronary by-pass surgery. While being quite effective and having evolvedto a relatively high degree of safety for an invasive procedure, by-passsurgery still involves potentially serious complications and generallyresults in an extended recovery period.

With the advent of percutaneous transluminal coronary angioplasty (PTCA)in 1977, the scene changed dramatically. Using catheter techniquesoriginally developed for heart exploration, inflatable balloons weredeployed to re-open occluded regions in arteries. The procedure wasrelatively non-invasive, took a short time compared to by-pass surgeryand recovery time was minimal. However, PTCA brought with it its ownproblems including vasospasm, elastic recoil of the stretched arterialwall and restenosis, the re-clogging of the treated artery due toneointimal hyperplasia in the vicinity of the procedure, any of whichcould undo much of what had been accomplished.

The next improvement, advanced in the mid-1980s, was the use of a stentto maintain a luminal diameter that had been re-established using PTCA.This for all intents and purposes put an end to vasospasm and elasticrecoil but did not resolve the issue of restenosis. That is, prior tothe introduction of stents, restenosis occurred in about 30 to 50% ofpatients undergoing PTCA. Stenting reduced this to about 15 to 30%, asubstantial improvement but still more than desirable.

In 2003, the drug-eluting stent (DES) was introduced. The drugsinitially used with DESs were cytostatic compounds, that is, compoundsthat curtailed the proliferation of cells that fostered restenosis. WithDESs, the occurrence of restenosis was reduced to about 5 to 7%, arelatively acceptable figure. However, the use of DESs engendered yetanother complication, late stent thrombosis, the forming of blood clotsat some time after the stent was in place. It was hypothesized that theformation of blood clots was most likely due to delayed healing, aside-effect of the use of cytostatic drugs. Thus, other types of drugswere sought to reduce the incidence of late stent thrombosis as well asother complications related to the use of cytostatic agents. A promisingsolution was found in the anti-proliferative family of compounds, inparticular rapamycin and its derivatives, which appeared surprisinglyeffective. DESs comprising members of the rapamycin family of compoundswere extensively studied and several have become commercial products. Itwas found, however, that, due at least in part to the fact that thereare three conjugated double bonds in rapamycin and its pharmaceuticallyactive derivatives, the entire family of rapamycin derivative drugs issensitive to oxidative and free radical induced degradation. That is,oxygen in and around a DES containing the macrocyclic triene fosters theformation of radical species that in turn initiate auto-oxidation of thetriene moiety. The response to this negative property of the compoundswas obvious to those skilled in the art: protect the rapamycinderivatives by including a pharmaceutically acceptable antioxidant withthe drug both as an isolated solid as synthesized and purified and in adrug reservoir layer containing the rapamycin derivative on a DES.

The problem is that many antioxidants including those suitable for useon DESs are not particularly salutary to patients. This, together withthe fact that, once fabricated and packaged in an essentiallyoxygen-free atmosphere protected from light, rapamycin derivative drugsare actually reasonably stable suggests that, in addition to in generalreducing the exposure of the drug to harsh processing conditions, itwould be beneficial to have an antioxidant present during thefabrication of a rapamycin derivative-containing DES but have a littleas possible remaining once the DES is mounted on a carrier vehicle,sterilized and packaged in a light-tight, inert atmosphere container oronce the DS has been implanted in a patient. The present inventionprovides a method of accomplishing this goal.

SUMMARY

Thus, in one aspect this invention relates to a method of fabricating animplantable medical device comprising a rapamycin derivative drug, themethod comprising:

synthesizing a rapamycin derivative drug;purifying the rapamycin derivative drug using a technique that resultsin substantially pure rapamycin derivative drug dissolved in a solvent,wherein:

the solvent used in the purification technique is suitable forpreparation of a coating composition comprising the rapamycin derivativedrug;

determining the percent by weight of the rapamycin derivative in thesolvent;adjusting the amount of solvent such that the weight percent rapamycinderivative drug in the solvent is that desired in a coating compositionto be applied to an implantable medical device;adding a desired weight percent, based on the weight of rapamycinderivative drug, of an pharmaceutically acceptable antioxidantstabilizer to form the coating composition; anddisposing the coating composition on the implantable medical device toform a drug reservoir layer.

In an aspect of this invention, the method herein further comprisesaddition of a matrix polymer to the coating composition before disposingthe composition on an implantable medical device.

In an aspect of this invention, the method herein further comprisesdrying the drug reservoir layer.

In an aspect of this invention, the method herein further comprisesmounting the implantable medical device on a carrier vehicle.

In an aspect of this invention, the carrier vehicle is a catheter.

In an aspect of this invention, the carrier vehicle with mountedimplantable device is sterilized.

In an aspect of this invention, sterilization comprises ethylene oxidesterilization, e-beam sterilization or gamma sterilization.

In an aspect of this invention, the sterilized deliverydevice/implantable device is packaged in a light-tight container underan inert atmosphere.

In an aspect of this invention, the synthesized rapamycin drug isselected from the group consisting of a 40-O-substituted rapamycin,everolimus, temsirolimus, deforolimus, ridaforolimus, merilimus,biolimus, umirolimus and 16-pent-2-ynyloxy-32(S)-dihydrorapamycin.

In an aspect of this invention, the synthesized rapamycin drug isselected from the group consisting of zotarolimus, ABT-578, a16-O-substituted rapamycin, novolimus, or myolimus.

In an aspect of this invention, the antioxidant stabilizer is selectedfrom the group consisting of a butylated phenol, butylatedhydroxytoluene (BHT), butylated hydroxyanisole, t-butylhydroquinone,quinone, an alkyl gallate, methyl gallate, ethyl gallate, propylgallate, octyl gallate, docecyl gallate, resveratrol, cysteine,n-acetylcysteine, bucillamine, glutathione, 7-hydroxyethylrutoside,carvedilol, vitamin C, ascorbyl palmitate, fumaric acid, a tocopherol,α-tocopherol, α-tocopherol acetate, a tocotrienol, vitamin E, lycopene,a flavonoid, a carotenoid, carotene and combinations thereof.

In an aspect of this invention, the antioxidant stabilizer is BHT.

In an aspect of this invention, purifying the synthesized rapamycinderivative drug is selected from the group consisting of elution(column) chromatography, high performance liquid chromatography, highperformance countercurrent chromatography, planar chromatography,supercritical fluid chromatography, liquid-liquid extraction andliquid-solid extraction.

In an aspect of this invention, the solvent involved in the purificationprocess that is also suitable as a the solvent for a coating compositionis selected from the group consisting of methanol, ethanol, propanol,n-propanol, isopropanol, butanol, pentane, hexane, heptane, octane,nonane, methyl acetate, ethyl acetate, propyl acetate, butyl acetate,toluene, xylene, acetone, methyl ethyl ketone (MEK), cyclopentanone,cyclohexanone, diethyl ether, dipropyl ether, diisopropyl ether,tetrahydrofuran, dioxane, dimethyl formamide, dimethylacetamide,dimethyl sulfoxide and combinations thereof.

In an aspect of this invention, adjusting the amount of solvent to agive a selected weight/weight percent rapamycin derivative drug insolvent comprises removing solvent or adding solvent to the coatingcomposition.

In an aspect of this invention, the polymer is selected from the groupconsisting of a polyester, poly(L-lactide), poly(D-lactide),poly(D,L-lactide), poly(meso-lactide), poly(L-lactide-co-glycolide),poly(D-lactide-co-glycolide), poly(D,L-lactide-co-glycolide),poly(meso-lactide-co-glycolide), poly(caprolactone),poly(L-lactide-co-caprolactone), poly(glycolide-co-caprolactone),poly(hydroxyvalerate), poly(hydroxybutyrate), poly(ethyleneglycol-co-butylene terephthalate), poly(n-butyl methacrylate), afluoropolymer, poly(vinylidene fluoride-co-hexafluoropropylene) andblends and copolymer thereof.

In an aspect of this invention, the polymer is poly(vinylidenefluoride-co-hexafluoropropylene).

In an aspect of this invention, disposing the coating composition on theimplantable medical device to form a drug reservoir layer comprisesspray coating.

In an aspect of this invention, the implantable medical device is astent.

In an aspect of this invention, the rapamycin derivative drug iseverolimus.

In an aspect of this invention, the weight percent BHT based on theweight of everolimus present on the stent is 0.001 to 0.1%.

In an aspect of this invention, the amount of BHT remaining on the stentafter all of the process steps are completed is non-detectable.

DETAILED DESCRIPTION Brief Description of the Figures

FIG. 1 is a flow chart showing a prior art process for bringing arapamycin derivative from synthesis to disposition on a DES and finalpackaging in a light-tight container under an inert atmosphere.

FIG. 2 is a flow chart showing the process of this invention forbringing a rapamycin derivative from synthesis to disposition on a DESand final packaging in a light-tight container under an inertatmosphere.

DISCUSSION

Use of the singular herein includes the plural and vice versa unlessexpressly otherwise stated. That is, “a” and “the” refer to one or moreof whatever the word modifies. For example, “a pharmaceuticallyacceptable antioxidant” includes one such oxidant, two such oxidants or,under the right circumstances, an even greater number of antioxidants.By the same token, words such as, without limitation, “coatings” and“layers” refer to one coating or layer as well as to a plurality ofcoatings or layers unless, again, it is expressly stated or obvious fromthe context that such is not intended.

As used herein, words of approximation such as, without limitation,“about” “substantially,” “essentially” and “approximately” mean that thefeature so modified need not be exactly that which is expresslydescribed but may vary from that written description to some extent. Theextent to which the description may vary will depend on how great achange can be instituted and have one of ordinary skill in the artrecognize the modified feature as still having the requiredcharacteristics and capabilities of the unmodified feature. In general,but subject to the preceding discussion, a numerical value herein thatis modified by a word of approximation such as “about” may vary from thestated value by ±15%.

As used herein, an “implantable medical device” refers to any type ofappliance that is totally or partly introduced, surgically or medically,into a patient's body or by medical intervention into a natural orifice,and which is intended to remain there after the procedure. The durationof implantation may be essentially permanent, i.e., intended to remainin place for the remaining lifespan of the patient; until the device isphysically removed; or until the device biodegrades usually as theresult of the intentional use of a biodegradable substance for thefabrication of the device such that the device degrades over apredetermined time-span. Examples of implantable medical devicesinclude, without limitation, implantable cardiac pacemakers anddefibrillators; leads and electrodes for the preceding; implantableorgan stimulators such as nerve, bladder, sphincter and diaphragmstimulators, cochlear implants; prostheses, vascular grafts,self-expandable stents, balloon-expandable stents, stent-grafts, grafts,artificial heart valves and cerebrospinal fluid shunts.

While implantable medical devices can serve several concurrent purposesand such are within the scope of this invention, an implantable medicaldevice specifically designed and intended solely for the localizeddelivery of a therapeutic agent is within the scope of this invention.

Described by this invention, however, are drug-device combinationproducts which have primarily a device function with an addedtherapeutic agent to mitigate a known complication of the device, namelythe occurrence of restenosis subsequent to implantation of a stent, apresently preferred implantable medical device of this invention, in avessel for the purpose of maintain the patency of the vessel after suchhas been mechanically re-established by, for example, PTCA.

A stent refers generally to a device used to hold tissue in place in apatient's body. Particularly useful stents, however, are those used forthe maintenance of the patency of a vessel in a patient's body when thevessel is narrowed or closed due to diseases or disorders including,without limitation, tumors (in, for example, bile ducts, the esophagus,the trachea/bronchi, etc.), benign pancreatic disease, coronary arterydisease, carotid artery disease and peripheral arterial disease such asatherosclerosis, restenosis and vulnerable plaque. Vulnerable plaque(VP) refers to a fatty build-up in an arterial wall thought to be causedby inflammation and atherosclerosis. The VP is covered by a thin fibrouscap that can rupture leading to blood clot formation. A stent can beused to strengthen the wall of the vessel in the vicinity of the VP andact as a shield against such rupture. A stent can be used, withoutlimitation, in the neurological, carotid, coronary, pulmonary, renal,iliac, femoral, popliteal, and tibial arteries as well as in biliaryapplications and other peripheral vasculatures. A stent can be used inthe treatment or prevention of disorders such as, without limitation,thrombosis, restenosis, hemorrhage, vascular dissection or perforation,vascular aneurysm, chronic total occlusion, claudication, anastomoticproliferation, bile duct obstruction and ureter obstruction.

In addition to the above uses, stents may also be employed for thelocalized delivery of therapeutic agents to specific treatment sites ina patient's body. In fact, therapeutic agent delivery may be the solepurpose of the stent or the stent may be primarily intended for anotheruse such as those discussed above with drug delivery providing anancillary benefit. A DES is a non-limiting example of an implantablemedical device of this invention. The primary purpose of a DES is tomaintain the patency of a vascular lumen, while the drug on the stentserves to mitigate medical conditions ancillary to the implantation ofthe stent.

A stent used for patency maintenance is usually delivered to the targetsite in a compressed state and then expanded to fit the vessel intowhich it has been inserted. Once at a target location, a stent may beself-expandable or balloon expandable. In any event, due to theexpansion of the stent, any coating thereon must be flexible and capableof elongation.

As used herein, “device body” refers to a fully formed implantablemedical with an outer surface to which no coating or layer of materialdifferent from that of which the device itself is manufactured has beenapplied. A common example of a device body is a bare metal stent (BMS),which, as the name implies, is a fully-formed, usable stent that has notbeen coated with a layer of any material different from the metal ofwhich it is made on any surface that is in contact with bodily tissue orfluids. Of course, device body refers not only to BMSs but to anyuncoated device regardless of what it is made. Device bodies comprisedof bioresorbable polymers and corrodible metals are also known.

Implantable medical devices made of virtually any material, i.e.,materials presently known to be useful for the manufacture ofimplantable medical devices and materials that may be found to be so inthe future, may be used in the method of this invention. For example,without limitation, an implantable medical device useful with thisinvention may be made of one or more biocompatible metals or alloysthereof including, but not limited to, cobalt-chromium alloy (ELGILOY,L-605), cobalt-nickel alloy (MP-35N), 316L stainless steel, highnitrogen stainless steel, e.g., BIODUR 108, nickel-titanium alloy(NITINOL), tantalum, platinum, platinum-iridium alloy,iron-platinum-chromium alloy, gold and combinations thereof.

Implantable medical devices may also be made of polymers that arebiocompatible and biostable or biodegradable, the latter term includingbioabsorbable, bioresorbable and bioerodable.

As used herein, a “biocompatible” polymer refers to a polymer whereinboth its chemically intact, as synthesized, form and its degradationproducts are not, or at least are minimally toxic to living tissue; donot, or at least minimally and reparably injure living tissue; and donot, or at least minimally and controllably causes an immunologicalreaction in living tissue. Biocompatible polymers of this invention maybe biostable or biodegradable where “biodegradable” simply means thatthe polymer will be decomposed over time when exposed to a physiologicalenvirons, i.e. to the conditions present in a patient's body such as pH,the presence of enzymes, body temperature, etc. “Biostable,” on theother hand, refers to a polymer that does not significantly break downunder physiological conditions for essentially the entire duration ofits residency in a patient's body.

Examples of biocompatible, relatively biostable polymers that may beused with an implantable medical device of this invention include,without limitation, polyacrylates, polymethacryates, polyureas,polyurethanes, polyolefins, polyvinylhalides, polyvinylidenehalides,polyvinylethers, polyvinylaromatics, polyvinylesters,polyacrylonitriles, polysiloxanes, alkyd resins and epoxy resins.

Biocompatible, biodegradable polymers include naturally-occurringpolymers such as, without limitation, collagen, gelatin, chitosan,alginate, fibrin, fibrinogen, cellulosics, starches, dextran, dextrin,hyaluronic acid, heparin, glycosaminoglycans, polysaccharides andelastin.

One or more synthetic or semi-synthetic biocompatible, biodegradablepolymers may also be used to fabricate an implantable medical devicebody of this invention. As used herein, a synthetic polymer refers toone that is created wholly in the laboratory while a semi-syntheticpolymer refers to a naturally-occurring polymer that has been chemicallymodified in the laboratory. Examples of synthetic biodegradable polymersinclude, without limitation, polyphosphazines, polyphosphoesters,polyphosphoester urethane, polyhydroxyacids, polyhydroxyalkanoates,polyanhydrides, polyesters, polyorthoesters, polyamino acids,polyoxymethylenes, poly(ester-amides) and polyimides.

Other biocompatible polymers that may be used to fabricate the device tobe coated with a macrocyclic triene lactone drug/antioxidant stabilizerdrug reservoir layer of this invention include, without limitations,polyesters, polyhydroxyalkanoates (PHAs), poly(ester amides) that mayoptionally contain alkyl, amino acid, PEG and/or alcohol groups,polycaprolactone, poly(L-lactide), poly(D,L-lactide),poly(D,L-lactide-co-PEG) block copolymers,poly(D,L-lactide-co-trimethylene carbonate), polyglycolide,poly(lactide-co-glycolide), polydioxanone (PDS), polyorthoester,polyanhydride, poly(glycolic acid-co-trimethylene carbonate),polyphosphoester, polyphosphoester urethane, poly(amino acids),polycyanoacrylates, poly(trimethylene carbonate), poly(iminocarbonate),polycarbonates, polyurethanes, copoly(ether-esters) (e.g. PEO/PLA),polyalkylene oxalates, polyphosphazenes, PHA-PEG, and combinationsthereof. The PHA may include poly(α-hydroxyacids), poly(β-hydroxyacid)such as poly(3-hydroxybutyrate) (PHB),poly(3-hydroxybutyrate-co-valerate) (PHBV), poly(3-hydroxyproprionate)(PHP), poly(3-hydroxyhexanoate) (PHH), or poly(4-hydroxyacid) such aspoly poly(4-hydroxybutyrate), poly(4-hydroxyvalerate),poly(4-hydroxyhexanoate), poly(hydroxyvalerate), poly(tyrosinecarbonates), poly(tyrosine arylates), poly(ester amide),polyhydroxyalkanoates (PHA), poly(3-hydroxyalkanoates) such aspoly(3-hydroxypropanoate), poly(3-hydroxybutyrate),poly(3-hydroxyvalerate), poly(3-hydroxyhexanoate),poly(3-hydroxyheptanoate) and poly(3-hydroxyoctanoate),poly(4-hydroxyalkanaote) such as poly(4-hydroxybutyrate),poly(4-hydroxyvalerate), poly(4-hydroxyhexanote),poly(4-hydroxyheptanoate), poly(4-hydroxyoctanoate) and copolymersincluding any of the 3-hydroxyalkanoate or 4-hydroxyalkanoate monomersdescribed herein or blends thereof, poly(D,L-lactide), poly(L-lactide),polyglycolide, poly(D,L-lactide-co-glycolide),poly(L-lactide-co-glycolide), polycaprolactone,poly(lactide-co-caprolactone), poly(glycolide-co-caprolactone),poly(dioxanone), poly(ortho esters), poly(anhydrides), poly(tyrosinecarbonates) and derivatives thereof, poly(tyrosine ester) andderivatives thereof, poly(imino carbonates), poly(glycolicacid-co-trimethylene carbonate), polyphosphoester, polyphosphoesterurethane, poly(amino acids), polycyanoacrylates, poly(trimethylenecarbonate), poly(iminocarbonate), polyphosphazenes, silicones,polyesters, polyolefins, polyisobutylene and ethylene-alphaolefincopolymers, acrylic polymers and copolymers, vinyl halide polymers andcopolymers, such as polyvinyl chloride, polyvinyl ethers, such aspolyvinyl methyl ether, polyvinylidene halides, such as polyvinylidenechloride, polyacrylonitrile, polyvinyl ketones, polyvinyl aromatics,such as polystyrene, polyvinyl esters, such as polyvinyl acetate,copolymers of vinyl monomers with each other and olefins, such asethylene-methyl methacrylate copolymers, acrylonitrile-styrenecopolymers, ABS resins, and ethylene-vinyl acetate copolymers,polyamides, such as Nylon 66 and polycaprolactam, alkyd resins,polycarbonates, polyoxymethylenes, polyimides, polyethers, poly(glycerylsebacate), poly(propylene fumarate), poly(n-butyl methacrylate),poly(sec-butyl methacrylate), poly(isobutyl methacrylate),poly(tert-butyl methacrylate), poly(n-propyl methacrylate),poly(isopropyl methacrylate), poly(ethyl methacrylate), poly(methylmethacrylate), epoxy resins, polyurethanes, rayon, rayon-triacetate,cellulose acetate, cellulose butyrate, cellulose acetate butyrate,cellophane, cellulose nitrate, cellulose propionate, cellulose ethers,carboxymethyl cellulose, polyethers such as poly(ethylene glycol) (PEG),copoly(ether-esters) (e.g. poly(ethylene oxide-co-lactic acid)(PEO/PLA)), polyalkylene oxides such as poly(ethylene oxide),poly(propylene oxide), poly(ether ester), polyalkylene oxalates,phosphoryl choline containing polymer, choline, poly(aspirin), polymersand co-polymers of hydroxyl bearing monomers such as 2-hydroxyethylmethacrylate (HEMA), hydroxypropyl methacrylate (HPMA),hydroxypropylmethacrylamide, PEG acrylate (PEGA), PEG methacrylate,methacrylate polymers containing2-methacryloyloxyethyl-phosphorylcholine (MPC) and n-vinyl pyrrolidone(VP), carboxylic acid bearing monomers such as methacrylic acid (MA),acrylic acid (AA), alkoxymethacrylate, alkoxyacrylate, and3-trimethylsilylpropyl methacrylate (TMSPMA),poly(styrene-isoprene-styrene)-PEG (SIS-PEG), polystyrene-PEG,polyisobutylene-PEG, polycaprolactone-PEG (PCL-PEG), PLA-PEG,poly(methyl methacrylate)-PEG (PMMA-PEG), polydimethylsiloxane-co-PEG(PDMS-PEG), poly(vinylidene fluoride)-PEG (PVDF-PEG), PLURONIC™surfactants (polypropylene oxide-co-polyethylene glycol),poly(tetramethylene glycol), hydroxy functional poly(vinyl pyrrolidone),biomolecules such as collagen, chitosan, alginate, fibrin, fibrinogen,cellulose, starch, dextran, dextrin, hyaluronic acid, fragments andderivatives of hyaluronic acid, heparin, fragments and derivatives ofheparin, glycosamino glycan (GAG), GAG derivatives, polysaccharide,elastin, elastin protein mimetics, or combinations thereof. Someexamples of elastin protein mimetics include (LGGVG)_(n), (VPGVG)_(n),Val-Pro-Gly-Val-Gly, or synthetic biomimeticpoly(L-glytanmate)-b-poly(2-acryloyloxyethyllactoside)-b-poly(l-glutamate)triblock copolymer.

In some embodiments of the current invention the polymer used with thedevice and in the method of this invention can be poly(ethylene-co-vinylalcohol), poly(methoxyethyl methacrylate), poly(dihydroxylpropylmethacrylate), polymethacrylamide, aliphatic polyurethane, aromaticpolyurethane, nitrocellulose, poly(ester amide benzyl),co-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,6-hexylenediester]_(0.75)-[N,N′-sebacoyl-L-lysine benzyl ester]_(0.25)} (PEA-Bz),co-poly-{[N,N′-sebacoyl-bis-(L-leucine)-1,6-hexylenediester]_(0.75)-[N,N′-sebacoyl-L-lysine-4-amino-TEMPO amide]_(0.25)}(PEA-TEMPO), aliphatic polyester, aromatic polyester, fluorinatedpolymers such as poly(vinylidene fluoride-co-hexafluoropropylene),poly(vinylidene fluoride) (PVDF), poly(vinylidenefluoride-co-hexafluoropropylene-co-tetrafluoroethylene), and Teflon™(polytetrafluoroethylene), a biopolymer such as elastin mimetic proteinpolymer, star or hyper-branched SIBS(styrene-block-isobutylene-block-styrene), or combinations thereof. Insome embodiments, where the polymer is a copolymer, it can be a blockcopolymer that can be, e.g., di-, tri-, tetra-, or oligo blockcopolymers or a random copolymer. In some embodiments, the polymer canalso be branched polymers such as star polymers.

Presently preferred polymers for use with this invention includepolyesters such as, without limitation, poly(L-lactide),poly(D-lactide), poly(D,L-lactide), poly(meso-lactide),poly(L-lactide-co-glycolide), poly(D-lactide-co-glycolide), poly(D,L-lactide-co-glycolide), poly(meso-lactide-co-glycolide),poly(caprolactone), poly(hydroxyvalerate), poly(hydroxybutyrate),poly(ethylene glycol-co-butylene terephthalate).

Other presently preferred polymers of this invention are fluoropolymerssuch as poly(vinylidene fluoride-co-hexafluoropropylene). When used, thepoly(vinylidene fluoride-co-hexafluoropropylene) preferable at presenthas a constitutional unit weight-to-weight (wt/wt) ratio of about 85:15.“Constitutional unit” refers to the composition of a monomer as itappears in a polymer. For example, without limitation, theconstitutional unit of the monomer acrylic acid, CH₂═CHC(O)OH, is—CH₂—CH(C(O)OH)— The average molecular weight of the presently preferredpoly(vinylidene fluoride-co-hexafluoropropylene) polymer is from about50,000 to about 500,000 Daltons. Further, it is presently preferred thatthe poly(vinylidene fluoride-co-hexafluoropropylene) polymer used toform a drug reservoir layer herein be semicrystalline. The presentlypreferred coating thickness of the poly(vinylidenefluoride-co-hexafluoropropylene) drug reservoir layer is from about 1 umto about 20 um.

Blends and copolymers of the above polymers may also be used and arewithin the scope of this invention. Based on the disclosures herein,those skilled in the art will recognize those implantable medicaldevices and those materials from which they may be fabricated that willbe useful with the coatings of this invention.

As used herein, a “primer layer” refers to a coating consisting of apolymer or blend of polymers that exhibit good adhesion characteristicswith regard to the material of which the device body is manufactured andgood adhesion characteristic with regard to whatever material is to becoated on the device body. Thus, a primer layer serves as anintermediary layer between a device body and materials to be affixed tothe device body and is, therefore, applied directly to the device body.Examples without limitation, of primers include acrylate andmethacrylate polymers with poly(n-butyl methacrylate) being a presentlypreferred primer. Some additional examples of primers include, but arenot limited to, poly(ethylene-co-vinyl alcohol), poly(vinylacetate-co-vinyl alcohol), poly(methacrylates), poly(acrylates),polyethyleneamine, polyallylamine, chitosan, poly(ethylene-co-vinylacetate), and parylene-C.

As used herein, “drug reservoir layer” refers either to a layer oftherapeutic agent applied neat or a therapeutic agent that has beendissolved or dispersed in a polymer matrix. A polymeric drug reservoirmatrix is designed such that, by one mechanism or another, e.g., withoutlimitation, by elution or as the result of biodegradation of thepolymer, the therapeutic substance is released from the layer into thesurrounding environment. A drug reservoir layer may also act as arelease rate-controlling layer.

In addition to an optional primer layer and a drug reservoir layer, animplantable medical device of this invention may comprise a topcoatlayer. As used herein, a “topcoat layer” refers to a polymeric layerthat is disposed over an implantable medical device of this inventionsuch that it comprises the outermost layer of polymer on the device,that is, it is the layer that is in direct contact with the environmentin which the device is implanted. A topcoat layer may be biodegradable,which biodegradation may occur relatively slowly if the layer is alsoserves as a rate controlling layer for the release of the macrocyclictriene lactone drug from the device, or biodegradation may occur rapidlyif the topcoat layer serves only as a protective layer for the layersbeneath. A topcoat layer may also serve as a compatibility-inducinglayer that renders the device more inert with regard to reaction withforeign body-eliminating mechanisms within the body.

As use herein, “disposing” a layer or material onto a particularsubstrate be it a device body or another layer, refers to a coating ofthe material applied directly to the exposed surface of the indicatedsubstrate. By “exposed surface” is meant any surface regardless of itsphysical location with respect to the configuration of the device that,in use, would be in contact with bodily tissues or fluids. “Disposing”may, however, also refer to the application of the layer onto anintervening layer that has been applied to a stent body, wherein thelayer is applied in such a manner that, were the intervening layer notpresent, the layer would be applied to the exposed surface of theindicated substrate. An example of an intervening layer is a primerlayer.

Drug eluting stents are also known in which neat drug is applied to allor a portion of the surface of a stent without a matrix polymer in thecoating composition. In some cases the surface of the stent to which theneat drug is to be applied is roughened or has features such as pits,depots or grooves to help retain the neat drug on the stent. Anotherembodiment of a DES that can benefit from the invention herein is ahollow or stent in which the hollow space is at least partially filledwith the drug, which then elutes out of the stent through pores createdin the surface of the stent.

As used herein, the terms “drug,” “therapeutic agent,” “active agent”and the like are interchangeable and refer to substances that have beenapproved by the Food and Drug Administration (FDA), overseas regulatoryagencies, notified bodies, or the USDA for use in treatment of diseasesand disorders in any animal species, but in particular human beings. Ingeneral, a drug, a therapeutic agent or an active agent refers to anysubstance that, when administered in a therapeutically effective amountto a patient suffering from a disease, has a therapeutic beneficialeffect on the health and well-being of the patient. A therapeuticbeneficial effect on the health and well-being of a patient includes,but it not limited to: (1) curing the disease; (2) slowing the progressof the disease; (3) causing the disease to retrogress; or, (4)alleviating one or more symptoms of the disease. As used herein, atherapeutic agent also includes any substance that when administered toa patient, known or suspected of being particularly susceptible to adisease, in a prophylactically effective amount, has a prophylacticbeneficial effect on the health and well-being of the patient. Aprophylactic beneficial effect on the health and well-being of a patientincludes, but is not limited to: (1) preventing or delaying on-set ofthe disease in the first place; (2) maintaining a disease at aretrogressed level once such level has been achieved by atherapeutically effective amount of a substance, which may be the sameas or different from the substance used in a prophylactically effectiveamount; or, (3) preventing or delaying recurrence of the disease after acourse of treatment with a therapeutically effective amount of asubstance, which may be the same as or different from the substance usedin a prophylactically effective amount, has concluded.

A “therapeutically effective amount” refers to that amount of atherapeutic agent that will have a beneficial effect, which may becurative or palliative, on the health and well-being of the patient withregard to the disease or disorder with which the patient is known orsuspected to be afflicted. A therapeutically effective amount may beadministered as a single bolus, as intermittent bolus charges, as short,medium or long term sustained release formulations or as any combinationof these. As used herein, short-term sustained release refers to theadministration of a therapeutically effective amount of a therapeuticagent over a period from about several hours to about 3 days.Medium-term sustained release refers to administration of atherapeutically effective amount of a therapeutic agent over a periodfrom about 3 day to about 14 days and long-term refers to the deliveryof a therapeutically effective amount over any period in excess of about14 days. Any reference a therapeutic agent relating to its presence onan implantable medical device or its use in a method of this inventionis to be understood as referring to a therapeutically effective amountof that therapeutic agent.

As used herein, “pharmaceutically acceptable” refers to a substance thathas been approved by the appropriate agency(ies) for use in animalspecies, again, in particular, human beings. This includes, of course,drugs but also includes other materials that, while not drugs per se,have a utility in animal species for other purposes. This includessubstances that been tested for safety and found to be “generallyregarded as safe” (GRAS) in animal species.

As used herein a “pharmaceutically acceptable antioxidant stabilizer”refers to a chemical substance that does not, at least in sufficientlylow doses, detrimentally affect the physiological well-being of apatient to whom it has been administered and that is capable ofpreventing damage to therapeutic agents due to reaction of the agentwith oxygen or free radicals released by reaction of oxygen with otherentities. For the purpose of this invention, a pharmaceuticallyacceptable antioxidant includes, without limitation, a butylated phenol,butylated hydroxytoluene (BHT), butylated hydroxyanisole (BHA),t-butylhydroquinone, quinone, an alkyl gallate, methyl gallate, ethylgallate, propyl gallate, octyl gallate, docecyl gallate, resveratrol,cysteine, n-acetylcysteine, bucillamine, glutathione,7-hydroxyethylrutoside, carvedilol, vitamin C, ascorbyl palmitate,fumaric acid, a tocopherol, α-tocopherol, α-tocopherol acetate, atocotrienol, vitamin E, lycopene, a flavonoid, a carotenoid andcarotene.

A presently preferred pharmaceutically acceptable antioxidant stabilizerfor use in device and methods herein is butylated hydroxytoluene (BHT).

As noted previously, antioxidants of the type used for the stabilizationof drugs herein are not particularly beneficial to patients.Significantly, this is not a great problem in theory. Once animplantable medical device has been fabricated and placed in protectivepackaging or once it has been implanted in a patient's body thereappears to be no further need of an antioxidant stabilizer. For example,a Xience Prime stent (Abbott Cardiovascular Systems, Inc.) in which thedrug reservoir layer comprises everolimus as the macrocyclic trienelactone drug and BHT as the antioxidant stabilizer and which is packagedin a light-tight package under an Argon atmosphere, shelf life studieshave shown that BHT is not necessary for product stability under longterm (25° C., 60% relative humidity) or intermediate (30° C., 65%relative humidity) storage conditions. Critical attributes of the coateddevice such as Total Content, Drug Release and Degradation Product havebeen found to be unaffected by the absence of BHT on the device. Thepreceding suggests that it would be beneficial to patients and notdetrimental to the modified rapamycin drug to minimize the amount ofantioxidant stabilizer on a finished, that is, fully fabricated,implantable medical device.

Thus, in co-pending patent application Ser. No. 13/788,584, whichapplication is filed on even date herewith and which is incorporated byreference as if fully set forth herein, it is taught that apharmaceutically acceptable antioxidant stabilizer may be included as acomponent of in one or more layers coated on an implantable medicaldevice in an amount by weight that totals about 0.0001% to about 0.01%of the total amount by weight of macrocyclic triene lactone (whichincludes the rapamycin derivatives of this invention) present on thedevice. The Ser. No. 13/788,584 application further teaches that, whenthe pharmaceutically acceptable antioxidant stabilizer is BHT, apresently preferred antioxidant stabilizer, the rapamycin derivative iseverolimus and the implantable medical device is a stent, to arrive at afinished catheter/stent product that has the desired amount of residualBHT, i.e., about 0.0001% to about 0.01% w/w based on the weight ofeverolimus on the stent, the amount of BHT in the initial coatingcomposition should be about 0.166% w/w BHT or less based on everolimus.Currently, however, everolimus is supplied commercially with 0.2% BHT(w/w), which amount is intended primarily to protect pure everolimus asan isolated solid prior to its incorporation into a coating composition.The present invention removes this requirement since pure everolimus isnever isolated as a dry solid permitting the initial amount of BHT to besubstantially reduced at all stages of fabrication of a DES comprisingeverolimus, which it is expected should result in a finished product,e.g., a sterilized stent mounted on a catheter delivery vehicle, with aresidual BHT content that is in the range set forth in the Ser. No.13/788,584 patent application or even lower, even to the point of beingnon-detectable. A further benefit of the procedure from synthesis tocoating and final packaging is that the rapamycin derivative is notisolated as a dry solid and is generally not exposed to any manner ofharsh treatment that could result in loss of purity or loss ofbiological activity.

There is a viable alternative to the primary method of this invention, amethod that more closely resembles the current procedure but stillavoids the isolation of dry rapamycin derivative and therefore is stillnovel over the prior art. In this procedure, the rapamycin derivative isrecrystallized from an appropriate solvent, in the case of everolimus,ethanol. The still solvent-wetted pure rapamycin derivative is thenwashed with a small amount of cold recrystallization solvent to removeany vestige of impurities. The recrystallization-solvent-wetted purerapamycin derivative is then immediately dissolved in an appropriatecoating composition solvent and an antioxidant added, again in the caseof everolimus, BHT. The remainder of this alternative mirrors theprocedure of this invention, as shown in FIG. 2, from this point on.

As used herein, a rapamycin derivative refers to rapamycin that hasundergone chemical modification at one or more positions on themolecule. Preparing such a rapamycin derivative is conventionallyreferred to as “synthesizing” the compound. At present, one preferredposition of the modification is the 40-O-position, as such is known andunderstood by those skilled in the art. Currently preferred40-O-rapamycin derivatives include everolimus, temsirolimus, deforolimus(ridaforolimus), merilimus and biolimus(umirolimus), although it isunderstood that other modified, including other 40-O-substituted,rapamycins may be used with the method of this invention and are withinthe scope hereof. Another preferred position of derivitization ofrapamycin is the 16-O-position which includes the rapamycin derivativenovolimus. Another useful rapamycin derivative is zotarolimus (AB-578).Lastly, there are useful therapeutic agents with biological activitysimilar to rapamycin, examples of which include myolimus and16-pent-2-ynyloxy-32(S)-dihydrorapamycin.

An important part of the rapamycin derivative synthesis process ispurification of the final product. This is necessary because of thestringent requirements imposed by regulatory agencies with regard toknowing specifically what and exactly how much of a particular drug isbeing administered to a patient. Thus, any synthesis of a rapamycinderivative will include one or more purification steps. It is an aspectof this invention that whatever purification method is selected for usein the rapamycin derivative synthesis, it should not require or resultin the isolation of the rapamycin derivative as a dry solid. Sincepurification methods such as, without limitation, elution (column)chromatography, high performance liquid chromatography, high performancecountercurrent chromatography, planar chromatography, supercriticalfluid chromatography, liquid-liquid extraction, liquid-solid extractionand the like, all of which are within the scope of this invention,result in the purified compound being dissolved in a solvent.

The selected solvent for the purification should, in addition to beingsuitable for the purification procedure itself, be suitable as a solventfor use in coating a drug reservoir layer on an implantable medicaldevice such as, without limitation, a DES.

A “coating composition” is simply a formulation comprising the selectedsolvent, the rapamycin derivative, the antioxidant stabilizer and anyother additives, excipients or adjuvants that might be desirable in adrug reservoir layer, each of which may be dissolved in or suspended inthe selected solvent. In particular, a polymer that will serve as amatrix for the rapamycin derivative drug may be included in the coatingcomposition.

As used herein, a “matrix polymer” refers to a polymer that has beenincluded in the coating composition and that serves as the carrier forthe components of the coating composition once the selected solvent hasbeen removed. The matrix polymer is selected in particular so as to havedesired drug release properties.

With regard to the selected solvent, to be “suitable” for a purificationprocess referred to herein means in general that the rapamycinderivative should initially be soluble in the chosen solvent. To besuitable as a solvent for the coating composition, the solvent shouldhave an appropriate volatility so that it can be readily removed fromthe drug reservoir layer once deposited on a device or, if notparticularly volatile, such as, without limitation, DMSO, bepharmaceutically acceptable in its own right so that residual solvent inthe drug reservoir layer is of no pharmacological significance. Withregard to this last possibility especially, it is presently preferredthat a solvent selected for the purification/coating composition alsomeet ICH Tripartite Guidelines for safety. Solvents that exhibit theabove characteristics and therefor may be suitable for use in thepresent method include, without limitation, methanol, ethanol, propanol,n-propanol, isopropanol, butanol, pentane, hexane, heptane, octane,nonane, methyl acetate, ethyl acetate, propyl acetate, butyl acetate,toluene, xylene, acetone, methyl ethyl ketone (MEK), cyclopentanone,cyclohexanone, diethyl ether, dipropyl ether, diisopropylether,tetrahydrofuran, dioxane, dimethyl formamide, dimethylacetamide anddimethyl sulfoxide.

In the coated drug reservoir layer, the rapamycin derivative of thisinvention may be essentially crystalline, essentially amorphous oranywhere in between. By “essentially crystalline” or “essentiallyamorphous” is meant that, while the bulk of a sample of the rapamycinderivative will exhibit the characteristics of crystallinity oramorphousness, a small amount of the other particle form may still bedetected in the sample. It is presently preferred that the rapamycinderivative be at least essentially amorphous, more preferably completelyamorphous within the detection limit of an appropriate method to detectcrystalline drug in a coating as, for example without limitation, bydifferential scanning calorimetry.

As mentioned previously, rapamycin derivatives are oxygen sensitive dueto the presence of the conjugated triene, i.e., three double bondslinked together by a single bond between the first and the second and asingle bond between the second and the third. Since it is desirable, ifnot essential, that the composition and quantity of an active agentbeing administered to a patient, regardless of the manner ofadministration, be accurately known, it is highly desirable to controlas well as possible any mechanism that might detrimentally affect theactive agent before it is administered. Oxidation of compounds often hassuch a detrimental effect on active agents and is to be controlled. Withregard to delivery of macrocyclic triene lactone active agents of thisinvention using implantable medical devices such as stents, a solutionto this problem lies in the inclusion of pharmaceutically acceptableantioxidant compounds in the drug reservoir layer during the fabricationof the device. As noted previously “pharmaceutically acceptable” as usedherein means that the antioxidants that are useful in this inventionhave been found acceptable for use in humans by the Food and DrugAdministration (FDA, in the United States; equivalent foreigngovernmental agencies would be charged with such approvals in theirrespective countries). Of course, antioxidants that may in the future befound acceptable for human use by the FDA are clearly within the scopeof this invention. Antioxidants curtail oxidation of macrocyclic trienelactones by several well-known mechanisms such as radical scavenging andcomplexation with pro-oxidation metal species. BHT, a presentlypreferred antioxidant for use with an implantable medical device of thisinvention, is of the former type, i.e., it functions as a free radicalscavenger.

If desired it is entirely possible, and in fact is an aspect of thisinvention, to include another therapeutic agent or agents along with therapamycin derivative on an implantable medical device hereof. If theother agent(s) are known to not be oxygen sensitive, then no changesneed be made to the disclosure herein of the amount of antioxidant touse. If, on the other hand, any of the additional therapeutic agents areknown to be oxygen sensitive, then the total amount of antioxidant usedmay be determined as set forth above except that the total amount ofmacrocyclic triene lactone plus the amount of any other oxygen sensitivetherapeutic agent(s) is used in the experiments performed to determinethe effect of the fabrication steps on the amount of antioxidantstabilizer consumed during each phase of the fabrication.

Among other therapeutic agents that may be suitable for use in thisinvention, anti-inflammatory compounds are particularly presentlypreferred. Suitable anti-inflammatory agents that can be used incombination with the macrocyclic triene lactpmes herein include, withoutlimitation, dexamethasone, dexamethasone acetate, clobetasol,alclofenac, alclometasone dipropionate, algestone acetonide, alphaamylase, amcinafal, amcinafide, amfenac sodium, amiprilosehydrochloride, anakinra, anirolac, anitrazafen, apazone, balsalazidedisodium, bendazac, benoxaprofen, benzydamine hydrochloride, bromelains,broperamole, budesonide, carprofen, cicloprofen, cintazone, cliprofen,clobetasol propionate, clobetasone butyrate, clopirac, cloticasonepropionate, cormethasone acetate, cortodoxone, deflazacort, desonide,desoximetasone, dexamethasone dipropionate, diclofenac potassium,diclofenac sodium, diflorasone diacetate, diflumidone sodium,diflunisal, difluprednate, diftalone, dimethyl sulfoxide, drocinonide,endrysone, enlimomab, enolicam sodium, epirizole, etodolac, etofenamate,felbinac, fenamole, fenbufen, fenclofenac, fenclorac, fendosal,fenpipalone, fentiazac, flazalone, fluazacort, flufenamic acid,flumizole, flunisolide acetate, flunixin, flunixin meglumine, fluocortinbutyl, fluorometholone acetate, fluquazone, flurbiprofen, fluretofen,fluticasone propionate, furaprofen, furobufen, halcinonide, halobetasolpropionate, halopredone acetate, ibufenac, ibuprofen, ibuprofenaluminum, ibuprofen piconol, ilonidap, indomethacin, indomethacinsodium, indoprofen, indoxole, intrazole, isoflupredone acetate,isoxepac, isoxicam, ketoprofen, lofemizole hydrochloride, lomoxicam,loteprednol etabonate, meclofenamate sodium, meclofenamic acid,meclorisone dibutyrate, mefenamic acid, mesalamine, meseclazone,methylprednisolone suleptanate, momiflumate, nabumetone, naproxen,naproxen sodium, naproxol, nimazone, olsalazine sodium, orgotein,orpanoxin, oxaprozin, oxyphenbutazone, paranyline hydrochloride,pentosan polysulfate sodium, phenbutazone sodium glycerate, pirfenidone,piroxicam, piroxicam cinnamate, piroxicam olamine, pirprofen,prednazate, prifelone, prodolic acid, proquazone, proxazole, proxazolecitrate, rimexolone, romazarit, salcolex, salnacedin, salsalate,sanguinarium chloride, seclazone, sermetacin, sudoxicam, sulindac,suprofen, talmetacin, talniflumate, talosalate, tebufelone, tenidap,tenidap sodium, tenoxicam, tesicam, tesimide, tetrydamine, tiopinac,tixocortol pivalate, tolmetin, tolmetin sodium, triclonide,triflumidate, zidometacin, zomepirac sodium, aspirin (acetylsalicylicacid), salicylic acid, corticosteroids, glucocorticoids, tacrolimus,pimecorlimus and prodrugs, co-drugs and combinations thereof.

Other therapeutic agents that may be suitable for use in the methodsherein include anti-neoplastic, antimitotic, antiplatelet, antifebrin,antithrombin, cytostatic and anti-proliferative agents.

Antineoplastic or anti-mitotic agents include, without limitation,paclitaxel, docetaxel, protaxel, methotrexate, azathioprine,vincristine, vinblastine, fluorouracil, doxorubicin hydrochloride, andmitomycin.

Antiplatelet, anticoagulant, antifibrin, and antithrombin agentsinclude, without limitation, sodium heparin, low molecular weightheparins, heparinoids, hirudin, argatroban, forskolin, vapiprost,prostacyclin, prostacyclin dextran, D-phe-pro-arg-chloromethylketone,dipyridamole, glycoprotein IIb/IIIa platelet membrane receptorantagonist antibody, recombinant hirudin and thrombin, thrombininhibitors such as Angiomax ä, calcium channel blockers such asnifedipine, colchicine, fish oil (omega 3-fatty acid), histamineantagonists, lovastatin, monoclonal antibodies (such as those specificfor Platelet-Derived Growth Factor (PDGF) receptors), nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist), nitric oxide or nitric oxidedonors, super oxide dismutases, super oxide dismutase mimetic,4-amino-2,2,6,6-tetramethylpiperidine-1-oxyl (4-amino-TEMPO) andestradiol.

Cytostatic or anti-proliferative agents include, without limitation,angiopeptin, angiotensin converting enzyme inhibitors such as captopril,cilazapril or lisinopril, calcium channel blockers such as nifedipine;colchicine, fibroblast growth factor (FGF) antagonists; fish oil(ω-3-fatty acid); histamine antagonists; lovastatin, monoclonalantibodies such as, without limitation, those specific forPlatelet-Derived Growth Factor (PDGF) receptors; nitroprusside,phosphodiesterase inhibitors, prostaglandin inhibitors, suramin,serotonin blockers, steroids, thioprotease inhibitors,triazolopyrimidine (a PDGF antagonist) and nitric oxide.

Other potentially useful therapeutic agents include, without limitation,alpha-interferon, genetically engineered epithelial cells, DNA and RNAnucleic acid sequences, antisense molecules, and ribozymes, antibodies,receptor ligands, enzymes, adhesion peptides, blood clotting factors,inhibitors or clot dissolving agents such as streptokinase and tissueplasminogen activator, antigens for immunization, hormones and growthfactors, oligonucleotides, retroviral vectors; antiviral agents;analgesics; anorexics; antihelmintics; antiarthritics, antiasthmaticagents; anticonvulsants; antidepressants; antidiuretic agents;antidiarrheals; antihistamines; antimigrain preparations; antinauseants;antiparkinsonism drugs; antipruritics; antipsychotics; antipyretics;antispasmodics; anticholinergics; sympathomimetics; xanthinederivatives; cardiovascular preparations including calcium channelblockers, beta-blockers such as pindolol, antiarrhythmics;antihypertensives; diuretics; vasodilators including general coronary;peripheral and cerebral; central nervous system stimulants; cough andcold preparations, including decongestants; hypnotics;immunosuppressives; muscle relaxants; parasympatholytics;psychostimulants; sedatives; tranquilizers; natural or geneticallyengineered lipoproteins; and restenosis reducing agents.

Thus, the method of this invention may comprise the following steps: Adesired rapamycin derivative is synthesized using synthetic chemicalreactions and procedure either currently well-known to those skilled inthe art or as may be uniquely arrived at to accomplish the desiredsynthesis. The rapamycin derivative is then purified using a method thatpermits the use of a solvent that has been determined to be suitable foruse in the purification per se, in the preparation of a coatingcomposition and in the application of the coating composition to animplantable medical device as discussed above. Such method may comprise,without limitation, elution (column) chromatography, high performanceliquid chromatography, high performance countercurrent chromatography,planar chromatography, supercritical fluid chromatography, liquid-liquidextraction and liquid-solid extraction. The purified rapamycinderivative is left in the solvent used for the purification. The amountof purified rapamycin derivative desired in the coating composition,usually as a weight percent rapamycin derivative in the coating solventis selected. The actual weight percent rapamycin derivative in thepurification solvent is determined and, if the percentages are not thesame, purification solvent is added to or removed from the mixturecontaining the rapamycin derivative. If solvent needs to be removed, itis preferable to do so under the mildest conditions possible.Distillation of the solvent under reduced pressure, i.e., vacuumdistillation, is a preferred method of removing solvent. The process mayrequire heating but the temperature should be carefully selected so asto not cause any degradation of the rapamycin derivative. The effect oftemperature on any particular rapamycin can, of course, be predeterminedempirically.

Once the percent rapamycin in the purification solvent is adjusted, anantioxidant stabilizer is added to the mixture as a weight percent basedon the amount of rapamycin derivative present. The result is a coatingcomposition ready for disposition on an implantable medical device. Itis possible, however, and is an aspect of this invention, that a polymerbe added to the coating composition. The polymer will act as a matrixwithin which the rapamycin derivative, the antioxidant and the otherexcipients, adjuvants and the like are suspended when solvent(s) is(are)removed. The polymer is selected so as to have desired mechanical,biological, and in the case of a bioresorbable polymer, degradationproperties and desired drug release properties for the selectedrapamycin derivative. Once again, these properties are either known orreadily determined by those skilled in the art and need not bespecifically described herein. Any such rapamycin derivative/polymercombination is within the scope of this invention as is the addition ofother excipients or other drugs or both.

The dissolved or dispersed rapamycin derivative drug is then applied toan implantable medical device by spray coating to form a drug reservoirlayer. Spray coating may comprise a one-pass process or a plurality ofpasses to achieve the desired coating thickness and quantity of drug onthe implantable device.

The spray coated implantable device is then dried at an elevatedtemperature, which, as above, is selected so as to have no detrimentaleffect on the rapamycin derivative drug, that is, a temperature that isempirically determined by experimentation to be acceptable.

The implantable medical device comprising at least the drug reservoirlayer is then mounted on a delivery vehicle and the mounteddevice/catheter is sterilized. The delivery vehicle can be any manner ofdevice intended to convey an implantable medical device to and, at theappropriate time, release the implantable medical device at a treatmentsite in a patient's body. In the case of a DES, the stent is usuallymounted on a catheter as the delivery vehicle.

Sterilization of the mounted device can be accomplished by ethyleneoxide sterilization, e-beam sterilization or gamma sterilization, all ofwhich are well-known to those skilled in the art and require no detaileddescription herein.

The sterilized device/carrier vehicle is then ready for use or forstorage as discussed above, i.e., in a light-tight package under aninert gas atmosphere.

The novelty of the present invention can readily be seen by comparingFIG. 1, the current process from synthesis of the rapamycin derivativeto the coating of a drug reservoir layer comprising the rapamycinderivative on an implantable medical device. For purposes of clarity andconcreteness, the following description is directed specifically toeverolimus as the rapamycin derivative, BHT as the pharmaceuticallyacceptable antioxidant stabilizer and a vascular stent as theimplantable medical device. It is to be understood, however, that thesame or obviously similar steps are expected to pertain to virtually anyrapamycin derivative. Thus, FIG. 1, Step 1 is directed to the actualsynthesis of everolimus. Step 2 is the purification of the everolimus byrecrystallization from an appropriate solvent system. For everolimus,the current preferred solvent system is a mixture of an ester, such as,without limitation, ethyl acetate, and a hydrocarbon such as, withoutlimitation, heptane. This process results in pure crystallineeverolimus. The pure crystalline everolimus is then dissolved in anothersolvent, presently an alcohol such as, without limitation, ethanol, anda desired amount of BHT is added to the solution (FIG. 1, Step 3). Theamount of BHT is presently preferred to be in the range of 0.01 to 0.5percent by weight based on the amount of everolimus in the solution;most preferably, and the amount of BHT combined with everolimus ascurrently commercially provided is about 0.2%. The alcohol solution isthen carefully added to a large volume of water over an extended periodof time resulting in the precipitate of everolimus/0.2% BHT from theethanol/water as an amorphous solid (FIG. 1, Step 3). The amorphoussolid is dried, packaged under inert atmosphere, and shipped to, forexample, a manufacturer of medical devices. In FIG. 1, Step 4, theeverolimus/BHT is re-dissolved in a solvent suitable for preparation ofa coating composition and for coating on a stent as a drug reservoirlayer. At this point it is possible to introduce a polymer to thecoating composition to act as a matrix for the suspension of all thecomponents of the coating composition once the solvent is removed.Finally, in FIG. 1, Step 5, the coating composition is applied to thestent to form a drug reservoir layer. This final step may include othersub-steps such as the application of a topcoat layer, etc. but thesesteps, for the purposes of this example may be considered to beidentical for both FIG. 1 and FIG. 2, are well-known to those skilled inthe art and need not be discussed at length here.

In stark contrast to the above, FIG. 2, the novel process of thisinvention, consists essentially of the following steps:

FIG. 2, Step 1, is the same as FIG. 1, Step 1: synthesis of everolimus.In FIG. 1, Step 2, however, the processes diverge. Whereas FIG. 1, Step.2 was a recrystallization step, which by it nature requires isolation ofthe crystallized everolimus from impurities remaining in therecrystallization solvent, FIG. 2, Step 2 involves a purificationprocedure that results in pure everolimus dissolved in the purificationsolvent. Such purification techniques include, without limitation,elution (column) chromatography, high performance liquid chromatography,high performance countercurrent chromatography, planar chromatography,supercritical fluid chromatography, liquid-liquid extraction andliquid-solid extraction. The critical factor is that the selectedtechnique results in pure everolimus dissolved in solvent. As mentionedpreviously, the solvent should be one that is suitable for use in acoating composition and actual application of a coating to a stent. Inany event, in FIG. 2, Step 3, the amount of everolimus as a weightpercent of the total everolimus/solvent solution is determined and aselected amount of BHT is added. If desired a selected amount of amatrix polymer may also be added at this step. The percent everolimusdesired in the coating composition is then achieved by adding to orremoving solvent from the everolimus/BHT/optional polymer solution. Ofcourse, other solvents, excipients, additives, active agents, etc. incalculated amounts may also be added at this step. In any event, theresult of FIG. 2, Step 2, is a coating composition ready for applicationto a stent. In FIG. 2, Step 3, the coating composition is applied to thestep and then, as with in FIG. 1, additional steps are carried out suchas drying the applied coating to form drug reservoir layer, mounting thestent on a catheter, sterilizing the entire assembly and finallypackaging the assembly in a light-tight, container under an inertatmosphere, wherein, as discussed above, the everolimus has been shownto be sufficiently stable for storage.

As is readily apparent, the inventive process of FIG. 2 requires fewerseparate steps, less manipulation of rapamycin derivative drugs,especially in the dry state, and is substantially more gentle on theeverolimus that the current process as set forth in FIG. 1.

1-24. (canceled)
 25. A method of fabricating an implantable medicaldevice comprising a rapamycin derivative drug, the method consistingessentially of: synthesizing a rapamycin derivative drug; purifying therapamycin derivative drug using a technique that results in asubstantially pure rapamycin derivative drug dissolved in a solvent,wherein: the rapamycin derivative drug remains dissolved in the solventand is used for preparation of a coating composition comprising therapamycin derivative drug; adjusting the amount of the solvent such thatthe weight percent of the rapamycin derivative drug in the solvent isthat desired in the coating composition to be applied to an implantablemedical device; adding a desired weight percent, based on the weight ofthe rapamycin derivative drug, of an pharmaceutically acceptableantioxidant stabilizer to form the coating composition; and disposingthe coating composition on the implantable medical device to form a drugreservoir layer.
 26. The method of claim 25, wherein the synthesizedrapamycin derivative drug is selected from the group consisting of a40-O-substituted rapamycin, everolimus, temsirolimus, deforolimus,ridaforolimus, merilimus, biolimus, umirolimus,16-pent-2-ynyloxy-32(S)-dihydrorapamycin, zotarolimus, novolimus, andmyolimus.
 27. The method of claim 25, wherein the pharmaceuticallyacceptable antioxidant stabilizer is selected from the group consistingof a butylated phenol, butylated hydroxytoluene (BHT), butylatedhydroxyanisole, t-butylhydroquinone, quinone, an alkyl gallate, methylgallate, ethyl gallate, propyl gallate, octyl gallate, docecyl gallate,resveratrol, cysteine, n-acetylcysteine, bucillamine, glutathione,7-hydroxyethylrutoside, carvedilol, vitamin C, ascorbyl palmitate,fumaric acid, a tocopherol, α-tocopherol, α-tocopherol acetate, atocotrienol, vitamin E, lycopene, a flavonoid, a carotenoid, caroteneand combinations thereof.
 28. The method of claim 27, wherein thepharmaceutically acceptable antioxidant stabilizer is BHT.
 29. Themethod of claim 25, further comprising addition of a matrix polymer tothe coating composition before disposing the composition on theimplantable medical device, wherein the matrix polymer is selected fromthe group consisting of a polyester, poly(L-lactide), poly(D-lactide),poly(D,L-lactide), poly(meso-lactide), poly(L-lactide-co-glycolide),poly(D-lactide-co-glycolide), poly(D,L-lactide-co-glycolide),poly(meso-lactide-co-glycolide), poly(caprolactone),poly(L-lactide-co-caprolactone), poly(glycolide-co-caprolactone),poly(hydroxyvalerate), poly(hydroxybutyrate), poly(ethyleneglycol-co-butylene terephthalate), poly(n-butyl methacrylate), afluoropolymer, poly(vinylidene fluoride-co-hexafluoropropylene) andblends and copolymer thereof.
 30. The method of claim 28, wherein theweight percent BHT based on the weight of the rapamycin derivative drugpresent on the stent is about 0.001 to about 0.01%.
 31. A method offabricating an implantable medical device comprising a rapamycinderivative drug, the method comprising: a) synthesizing the rapamycinderivative drug; b) recrystallizing the rapamycin derivative drug froman appropriate recrystallization solvent; c) washing therecrystallization-solvent-wetted pure rapamycin derivative drug; d)dissolving the recrystallization-solvent-wetted pure rapamycinderivative drug immediately in an appropriate coating compositionsolvent; e) adding a desired weight percent, based on the weight ofrapamycin derivative drug, of a pharmaceutically acceptable antioxidantstabilizer to form the coating composition; and f) disposing the coatingcomposition on the implantable medical device to form a drug reservoirlayer.
 32. The method of claim 31 where the rapamycin derivative drug iseverolimus.
 33. The method of claim 31 where therecrystallization-solvent-wetted pure rapamycin derivative drug iswashed with a small amount of a cold recrystallization solvent.
 34. Themethod of claim 31 where the appropriate recrystallization solvent isethanol.
 35. The method of claim 32 where therecrystallization-solvent-wetted pure everolimus is washed with a smallamount of a cold recrystallization solvent.
 36. The method of claim 32where the appropriate recrystallization solvent is ethanol.
 37. Themethod of claim 32 where the pharmaceutically acceptable antioxidantstabilizer is BHT.
 38. A method of fabricating an implantable medicaldevice comprising a rapamycin derivative drug, the method comprising:purifying the rapamycin derivative drug using a technique that resultsin a substantially pure rapamycin derivative drug dissolved in asolvent, wherein: the solvent used in the purification technique is usedfor preparation of a coating composition comprising the rapamycinderivative drug; adjusting the amount of the solvent such that theweight percent of the rapamycin derivative drug in the solvent is thatdesired in the coating composition to be applied to an implantablemedical device; adding a desired weight percent, based on the weight ofthe rapamycin derivative drug, of an pharmaceutically acceptableantioxidant stabilizer to form the coating composition; and disposingthe coating composition on the implantable medical device to form a drugreservoir layer; wherein the substantially pure rapamycin derivativedrug is not isolated as a dry solid after the purifying step and beforethe disposing step.
 39. The method of claim 38, wherein the synthesizedrapamycin derivative drug is selected from the group consisting of a40-O-substituted rapamycin, everolimus, temsirolimus, deforolimus,ridaforolimus, merilimus, biolimus, umirolimus,16-pent-2-ynyloxy-32(S)-dihydrorapamycin, zotarolimus,16-pent-2-ynyloxy-32(S)-dihydrorapamycin, novolimus, and myolimus. 40.The method of claim 38, wherein the pharmaceutically acceptableantioxidant stabilizer is selected from the group consisting of abutylated phenol, butylated hydroxytoluene (BHT), butylatedhydroxyanisole, t-butylhydroquinone, quinone, an alkyl gallate, methylgallate, ethyl gallate, propyl gallate, octyl gallate, docecyl gallate,resveratrol, cysteine, n-acetylcysteine, bucillamine, glutathione,7-hydroxyethylrutoside, carvedilol, vitamin C, ascorbyl palmitate,fumaric acid, a tocopherol, α-tocopherol, α-tocopherol acetate, atocotrienol, vitamin E, lycopene, a flavonoid, a carotenoid, caroteneand combinations thereof.
 41. The method of claim 40, wherein thepharmaceutically acceptable antioxidant stabilizer is BHT.
 42. Themethod of claim 38, wherein the implantable medical device is a stent.43. The method of claim 42, wherein the rapamycin derivative drug iseverolimus or novolimus.
 44. The method of claim 43, wherein when therapamycin derivative drug is everolimus, the weight percent BHT based onthe weight of everolimus present on the stent is about 0.001 to about0.01%; and wherein when the rapamycin derivative drug is novolimus, theweight percent BHT based on the weight of novolimus present on the stentis about 0.001 to about 0.01%.
 45. The method of claim 43, wherein theamount of BHT remaining on the stent after all of the process steps arecompleted is non-detectable.